Among the newer cephalosporin antibiotics introduced into clinical medicine is cefaclor. Cefaclor is a broad spectrum antibiotic which is administered orally and is highly effective in the treatment of human infections. Cefaclor, known chemically as 7-D-phenylglycylamido-3-chloro-3-cephem-4-carboxylic acid, is described and claimed in U.S. Pat. No. 3,925,372. Cefaclor can be prepared by the acylation of the "3-chloro nucleus", 7-amino-3-chloro-3-cephem-4-carboxylic acid or an ester thereof. The 3-chloro nucleus in the free amino acid form is represented by the following formula ##STR1##
This nucleus, and the esters thereof, are valuable intermediates useful in the overall synthesis of cefaclor and in the preparation of other 3-halo substituted cephalosporins. The 3-chloro nucleus and other 3-halo nuclei are claimed and described in U.S. Pat. No. 4,064,343.
Prior to the present invention the 3-chloro nucleus was obtained by the N-deacylation of a 7-acylamino-3-chloro cephalosporin ester as described by U.S. Pat. No. 4,064,343. While 7-acylamino-3-chloro cephalosporins are prepared by chlorinating a 7-acylamino-3-hydroxy cephalosporin with phosphorus trichloride in DMF, the chlorination of a 7-amino-3-hydroxy cephalosporin ester with PCl.sub.3 /DMF results in the formation of a 7-[(dimethylaminomethylene)amino]3-chloro nucleus ester. The dimethylaminomethylene group, however, proved refractory to numerous cleavage attempts. Because of the importance of these cephalosporin nuclei, alternative routes to their preparation can be of significance in the commercial manufacture of the 3-halo substituted cephalosporin antibiotics.
The present invention provides an alternative process for the preparation of the 3-chloro nucleus. In particular, it provides a process for the direct conversion of a 7-amino-3-hydroxy-3-cephem-4-carboxylic acid ester, the "3-hydroxy nucleus" to the readily hydrolyzed N-formyl derivative of the 3-chloro nucleus.